Overcoming the Scarcity of Big Numbers

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Overcoming the Scarcity of Big Numbers

• Isaac Zak Kohane, MD, PhD
• HMS Center for Biomedical Informatics

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Overview

• Dire consequences of insufficiently powered
  studies
• The opportunity to leverage existing information
  sources to achieve the requisite sample sizes.
• The annotation challenge that remains.

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One Very Old Biomarker

• 1410 original articles on PSA screening for
  cancer
• 179 review articles
• With 1000s of gene products, how do we
  systematically address this problem?

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The paper that Launched at 100,000 chips
Alizadeh 2000
Alizadeh et al.
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Example Shipp 2002
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Example Rosenwald
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Example PPARg Pro12Ala and diabetes
Oh et al.
Deeb et al.
Mancini et al.
Clement et al.
Hegele et al.
Hasstedt et al.
Lei et al.
Ringel et al.
Sample size
Hara et al.
Overall P value 2 x 10-7 Odds ratio 0.79
(0.72-0.86)
Meirhaeghe et al.
Douglas et al.
Altshuler et al.
Mori et al.
All studies
Estimated risk (Ala allele)
0.2
0.4
0.6
0.8
1
1.2
2.0
1.4
1.6
1.8
0.1
0.3
0.5
0.7
0.9
1.1
1.3
1.5
1.7
1.9
Ala is protective
Courtesy J. Hirschhorn
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Peer SPIN Node
User
Childrens Hospital
Peer SPIN Node
Indiana
Peer SPIN Node
Peer SPIN Node
HTTP
Peer SPIN Node
Query Composer
Peer SPIN Node
MGH
Peer SPIN Node
Pittsburgh
Peer SPIN Node
UCLA(1)
Peer SPIN Node
HCNR
Beth Israel
UCLA(2)
Peer SPIN Node
Pathology
Peer SPIN Node
Node Tools
UPDATE
Clinical
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Aggregate-able and delegated approval
Researcher enters through web browser
HMS eCommons credentialing of researcher
Compose Web Query
HMS IRB approval for entire network
HMS Admin Supernode
Institutional Firewall
BWH MGH
CHMC
BIDMC
Institutional IRB approval to become a node
Different HIPAA-covered entities
Partners IRB Approval
Caregroup IRB Approval
CHMC IRB Approval
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True names the goal of biomarkers
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Triangulating Human Disease
Genetics
Physiology
Environment
Behavioral Social Milieu
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Substrate Gene Expression Omnibus

• Currently has 72,566 samples contained in 975
  series measured using 3136 platforms
• Gaining 2,500 samples per month
• 1200 curated data sets have been established
• Within each GDS, samples are directly comparable
• Most can be downloaded

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Substrate The Unified Medical Language System

• Label concepts using the Unified Medical Language
  System
• Largest unification of over 130 biomedical
  vocabularies
• Contains over one million inter-related concepts
• 20 million links between concepts
• Covers human and model organisms
• Scales from molecular, to physiological, to
  pathological

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Courtesy Atul Butte
Courtesy Atul Butte
Concepts CUI Synonyms and abbreviations Source
vocabulary and term Defined relations not
all Statistical relations not all, 4K for
diabetes mellitus
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Gene-Driven Nosology
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Biomarkers as Continuum
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Instance of multiplicity of biomarkers

• 11 genes related to aging concept
• G6PDH (with p lt 10-6)
• Individuals with G6PDH deficiency have been noted
  to have reduced mortality from cardiovascular
  disease and have increased longevity
• BDNF
• has been previously shown to have a significant
  drop in expression in human skin fibroblasts with
  aging.
• TNNT1, SYNJ1, TADA2L, SLC7A2, MGAT2 and KCTD2
  also associated with aging.

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Summary

• Adequate numbers of patient samples are ever more
  essential in the genomic era (big N).
• Distributed solutions for data sharing are
  workable today.
• Integrating the genome and phenome will require
  improved clinical annotation as well as big N

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Bioinformatics and Integrative Genomics (BIG)